Effect and mechanism of a subanesthetic dose of esketamine on postoperative neurocognitive disorders through the regulating of the TLR4/NF-κB pathway in microglia

IF 0.7 4区 材料科学 Q3 Materials Science
Yang Zhang, Mengying Xiong, Shibiao Chen, Ningyan Wang, Xiuhong Wang
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Abstract

Perioperative neurocognitive disorders (PND) are postoperative or anesthesia-related complications of the central nervous system, characterized by intelligence decline, memory loss, attention deficit, impaired decision-making skills, reduced language comprehension performance, and psychological disorders. This study aims to investigate the impact of a subanesthetic dose of esketamine on PND in aged mice by regulating the microglia toll-like receptor 4 (TLR4)/nuclear factor κB (NF-κB) pathway. An exploratory laparotomy model was established in 18-month-old C57BL/6 mice post-anesthesia. Behavioral evaluations such as open field tests and Morris water maze tests for autonomous activity and spatial learning and memory ability. Different esketamine doses were administered to aged mice, followed by behavioral assessment for autonomous activity and learning/memory abilities. Nucleic acid extraction employed magnetic nanoparticles, while qRT-PCR measured mRNA levels of tumor necrosis factor-α, interleukin-6, and interleukin-1β. Western Blot detected the Iba-1 and TLR4 protein expression and phosphorylation status of the P65 protein. Immunofluorescence determined the fluorescence intensity of Iba-1 and P-NF-κBp65. MTT assay evaluated cell viability. As a result, we demonstrated that a subanesthetic dose of esketamine effectively inhibited microglia activation and TLR4/NF-κB signaling pathway both in vivo and in vitro, resulting in decreased levels of inflammatory factors and improved neuroinflammatory responses, ultimately alleviating postoperative neurocognitive dysfunction. Notably, our findings revealed that laparotomy exploratory surgery-induced cognitive dysfunction, which can be improved by esketamine’s neuroprotective effects. Furthermore, our study also highlighted the protective effect of esketamine against lipopolysaccharide-induced inflammatory response in BV2 cells by inhibiting the TLR4/NF-κB signaling pathway.
通过调节小胶质细胞中的TLR4/NF-κB通路,亚麻醉剂量的艾司氯胺酮对术后神经认知障碍的影响及其机制
围手术期神经认知障碍(PND)是中枢神经系统的术后或麻醉相关并发症,表现为智力下降、记忆力减退、注意力缺陷、决策能力受损、语言理解能力下降和心理障碍。本研究旨在通过调节小胶质细胞收费样受体4(TLR4)/核因子κB(NF-κB)通路,研究亚麻醉剂量的埃斯氯胺酮对老年小鼠PND的影响。在麻醉后 18 个月大的 C57BL/6 小鼠中建立了探索性开腹手术模型。对小鼠的自主活动、空间学习和记忆能力进行行为评估,如开阔地测试和莫里斯水迷宫测试。给老龄小鼠注射不同剂量的埃斯卡胺,然后进行自主活动和学习/记忆能力的行为评估。核酸提取采用了磁性纳米颗粒,qRT-PCR测定了肿瘤坏死因子-α、白细胞介素-6和白细胞介素-1β的mRNA水平。Western Blot 检测了 Iba-1 和 TLR4 蛋白的表达以及 P65 蛋白的磷酸化状态。免疫荧光测定 Iba-1 和 P-NF-κBp65 的荧光强度。MTT 试验评估了细胞活力。结果表明,亚麻醉剂量的埃斯氯胺酮能有效抑制体内和体外的小胶质细胞活化和 TLR4/NF-κB 信号通路,从而降低炎症因子水平,改善神经炎症反应,最终缓解术后神经认知功能障碍。值得注意的是,我们的研究结果表明,开腹探查手术引起的认知功能障碍可以通过埃斯卡敏的神经保护作用得到改善。此外,我们的研究还强调了艾司氯胺酮通过抑制TLR4/NF-κB信号通路,对脂多糖诱导的BV2细胞炎症反应具有保护作用。
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来源期刊
Materials Express
Materials Express NANOSCIENCE & NANOTECHNOLOGY-MATERIALS SCIENCE, MULTIDISCIPLINARY
自引率
0.00%
发文量
69
审稿时长
>12 weeks
期刊介绍: Information not localized
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